There is little doubt that cocaine abuse in adults is associated with ischemic damage to the heart, intestine, kidney and brain. It has recently become apparent that lesions attributable to ischemia can also occur in the fetus of a cocaine-abusing mother. The pathophysiology of such lesions is poorly understood even in adults; information in the fetus is non-existent. We propose to study the effects of maternal administration of intravenous cocaine on blood flow to the brain of the fetus in utero using the fetal sheep as a model. We will compare effects in the fetus with effects int he newborn and pregnant adult, and we will compare effects on brain blood flow with effects on flow to other major organs. Specific Aim 1 proposes experiments that will test the hypotheses that the effects of cocaine are qualitatively similar in fetus and mother, that they are dose related, that they vary from one organ to another and that effects after a single dose differ from effects after "binge" administration. Specific Aim 2 proposes studies that will test the hypotheses that cocaine plasma levels will be lower in the fetus after maternal administration but that poor placental permeability to water soluble compounds will prolong the half-lives of fetal cocaine metabolites. Specific Aim 3 proposes experiments that will define mechanisms by which cocaine alters cerebral blood flow. We will test the hypotheses that cocaine causes dose-dependent changes in the diameter of pial vessels and that changes in pial vessel diameter are mediated by neurotransmitters. We will test the hypothesis that neurotransmitters influence vascular tone indirectly, by virtue of alterations in cerebral metabolism.